Abstract 4841: <i>SLC25A46</i> as a novel mitochondrial regulator and biomarker in breast cancer
Authors: Heather K. Beasley, Ky'Era V. Actkins, Tyne Miller-Flemming, Nancy J. Cox, Rachel Martini, Melissa B. Davis, Timothy Chu, Nicolas Robine, Bret C. Mobley, Antentor O. Hinton
Journal: Cancer Research (2023)

Abstract Triple-negative breast cancer (TNBC) is an aggressive, highly malignant breast cancer (BC) subtype further characterized by poor prognosis and chemoresistance. TNBC disproportionately affects African American and Latina women, where the differences in treatment efficacy cannot only be explained by social determinants of health. A better understanding of treatment outcomes requires a deep analysis of the ancestral-related underpinnings that affects treatment. Accounting for the role of ancestry in BC prognosis and progression, we hypothesize that ancestry has significant influences on BC etiology. Metabolic reprogramming of TNBC cells is shown to influence response to treatments. These distinct metabolic adaptations require the proper function of the mitochondrion, a highly dynamic organelle that coordinates and maintains the energetic demands of the cell. To this end, we sought to investigate novel proteins important in mitochondria function yet are understudied in BC phenotypes. SLC25A46 plays a significant role in regulating mitochondrial dynamics, cristae maintenance, and respiratory function. Although SLC25A46 poorly characterized, it has been demonstrated to interact with mitochondrial proteins, such as MFN-2 and OPA1, and the MICOS complex, making it an attractive pharmacological target. We were therefore interested if SLC25A46 has any potential as a target or biomarker in BC. First, we applied PrediXcan, a gene-based statistical algorithm, to calculate genetically predicted gene expression for SLC25A46 in 70,349 patients of European descent and 14,462 patients of African descent in BioVU, the Vanderbilt University Medical Center (VUMC) biorepository linked to de-identified electronic health records (EHRs). Models were built using RNA-seq data from the publicly available GTEX version 8 dataset. After fitting a multivariable logistic regression model to test SLC25A46 predicted expression against 1,704 phenotypes for each tissue, we observed that patients with high predicted expression were more likely to receive diagnosis of ‘abnormal findings in mammograms’ (P=2.76E-06, OR=2.26) or ‘lump or mass in breast’ (P=8.9E-06, OR=2.61) in the European descent group, which is well powered; however, we are not powered to replicate this finding in the African descent group. Therefore, we investigated SLC25A46 expression in an international RNAseq cohort enriched with women of African ancestry, including African Americans (AA), West and East Africans with TNBC (n=26). Interestingly, SLC25A46 shows significantly higher expression among self-reported AA than Ghanaian or Ethiopian women with TNBC (P=0.003). Thus, we postulated that these differences in SLC25A46 for patients of African ancestry might serve as a novel biomarker for cancer outcomes. Together, these data suggest that SLC25A46 has implications in BC as a novel target in cancer development, specifically in patients with admixed ancestry. Citation Format: Heather K. Beasley, Ky'Era V. Actkins, Tyne Miller-Flemming, Nancy J. Cox, Rachel Martini, Melissa B. Davis, Timothy Chu, Nicolas Robine, Bret C. Mobley, Antentor O. Hinton. SLC25A46 as a novel mitochondrial regulator and biomarker in breast cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4841.